Endocrine Abstracts

Introduction: Corticotroph pituitary adenomas that cause Cushing’s disease (CD) predominantly express the dopamine 2 receptor (D2) and somatostatin receptor subtype (sst) 5. The expression of sst2 is relatively low because of downregulating effects of high endogenous cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide is not effective in CD. To assess whether normalization of urinary free cortisol (UFC) excretion modulates the sst expression pattern, sst expression profiles of corticotroph adenomas from patients with normalized or elevated preoperative cortisol levels were compared. Moreover, the effects of pasireotide and octreotide on ACTH production were examined in vitro.

Methods: Corticotroph adenoma tissue was examined from patients from group 1 (n=11; mean duration of normocortisolism 10.3 weeks) and group 2 (n=21; elevated preoperative UFC). RT-PCR and immunohistochemical studies were performed to determine sst expression of these adenomas and to compare them to somatotroph adenomas (n=10).

Results: At mRNA level, adenomas from group 1 had tenfold higher sst2 expression levels compared to group 2 (P<0.01). Sst2 mRNA expression in group 1 was even comparable to that in somatotroph adenomas. There were no differences in sst5 and D2 mRNA expression levels between groups 1 and 2. At the protein level, no differences were found in sst2, sst5 or D2 receptor expression between group 1 (n=7) and 2 (n=5). Finally, octreotide was significantly less potent than pasireotide (both 10 nM) with respect to inhibition of ACTH secretion by adenomas of group 1 (−18.9±9.1% (n=4) vs. −36.3±11.2% (n=6); P<0.001).

Conclusion: After 10 weeks of normocortisolism induced by medical therapy, cortisol-mediated sst2-downregulation on corticotroph adenomas appears to be reversible at mRNA, but not yet at protein level. Octreotide remains less potent than pasireotide with respect to in vitro inhibition of ACTH secretion. This suggests that a sustained period of normocortisolism induced by medical therapy is required to induce re-expression of sst2 protein in corticotroph adenomas.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.